Variations in the vitamin D receptor gene may influence the clinical effects of low vitamin D levels in some chronic diseases, researchers found.

Action Points

Certain variations in the vitamin D receptor gene may influence the clinical effects of low vitamin D levels in some chronic diseases.

Note that patients in the cohort without the genetic polymorphism showed no association between low 25(OH)D levels and outcomes such as hip fracture, myocardial infarction, cancer, and death.

Variations in the vitamin D receptor gene may influence the clinical effects of low vitamin D levels in some chronic diseases, researchers found.

Among patients with low serum 25-hydroxyvitamin D (25(OH)D) in a U.S.-based cohort, the presence of one risk allele at rs7968585 was associated with a 40% increased risk for potentially fatal composite clinical outcomes, including hip fracture, myocardial infarction, cancer, and death (hazard ratio 1.40, 95% CI 1.12 to 1.74) according to Gregory Levin, PhD, of the University of Washington in Seattle, and colleagues.

The presence of two risk alleles was linked with an 82% increased risk (HR 1.82, 95% CI 1.31 to 2.54), they said.

However, patients in the cohort without the polymorphism showed no association between low 25(OH)D and these outcomes (HR 0.93, 95% CI 0.70 to 1.24), they wrote online in the Journal of the American Medical Association.

"The totality of these findings suggests that low [25(OH)D] concentration may be a modifiable risk factor for many chronic diseases," they wrote.

The researchers analyzed genetic variations in 304 patients with low 25(OH)D compared with 1,210 patients with normal concentrations enrolled in the Cardiovascular Health Study. They looked at the potential effects of those genetic variations on major health outcomes at 15 years of follow-up (median of 11 years).

Participants were white and mostly female (70%) with a mean age of 74, a mean 25(OH)D concentration of 26.7 ng/mL. They had a higher mean body mass index and were more likely to have diabetes or hypertension than those with normal vitamin D concentrations.

A total 948 participants (63%) experienced an event by the 15-year follow-up. Low 25(OH)D was associated with a 32% increased HR for composite adverse outcome (95% CI 1.13 to 1.54).

Without accounting for vitamin D concentration, the authors said there was no evidence in the cohort of main effect associations between either rs7968585 (HR per additional minor allele, 1.00, 95% CI 0.91 to 1.06, P=0.93) or rs2239179 (HR 0.93, 95% CI 0.85 to 1.02, P=0.13) and risk of the composite outcome.

The authors conducted a replication meta-analysis based on data from three additional cohorts -- the U.S. Health, Aging, and Body Composition (Health ABC) study, the Italian Invecchiare in Chianti, and the Swedish Uppsala Longitudinal Study of Adult Men.

Estimates for associations between low 25(OH)D and composite outcomes "were in the same direction in all four cohorts, but statistical significance was attained only in the Health ABC cohort."

Additional copies of risk alleles at rs7968585 were associated with an HR of 1.22 (95% CI 1.09 to 1.36) in the meta-analysis, they wrote.

The authors noted the study was limited by some heterogeneity in estimated interactions, lack of functional data to explore why variations affect 25(OH)D concentrations, lack of long-term measurements of 25(OH)D concentrations, and lack of generalizability of the study populations.

The Cardiovascular Health Study was funded by grants from the National Heart, Lung, and Blood Institute, the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, the National Center for Research Resources, the National Institute of Diabetes and Digestive and Kidney Diseases, and NIH.

The Health, Aging, and Body Composition study was funded by grants from the National Institute on Aging.

The genome-wide association study was funded by grants from the National Institute on Aging and NIH.

The baseline Invecchiare in Chianti study was supported by the Italian Ministry of Health, the National Institute on Aging, and NIH.

The Uppsala Longitudinal Study of Adult Men was supported by the Swedish Research Council, the Swedish Heart-Lung Foundation, the Thureus Foundation, and Uppsala University.

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